PROJECT SUMMARY Alzheimer?s disease (AD) is the most common progressive neurodegenerative disease responsible for cognitive impairment in elderly subjects. In AD, loss of neurons in the cerebral cortex and hippocampus is accompanied by extracellular deposition of A? plaques and neurofibrillary tangles of hyper phosphorylated tau. Currently, other than symptomatic therapies to maintain cerebrocortical activity and to modulate learning/cognition, there are no ways to stop the progression of the disease. Given the increased prevalence of the disease, there is an urgent need to develop therapies that can stop or slow down the progression of AD. Increased oxidative stress is implicated in the onset and progression of AD. Free radicals and reactive dicarbonyls under oxidative stress conditions irreversibly modify proteins forming proteolysis-resistant Advanced Glycation End products (AGEs) and have been implicated as causative agents in AD related cell dysfunction and degeneration. Normally, the Glyoxalase enzyme system (Glo-1), combined with glutathione (GSH), reduces oxidative stress and reactive dicarbonyls responsible for AGE formation. However, reduction in brain GSH levels increases oxidative stress and renders Glo-1 inactive. Unfortunately, GSH supplementation is highly inefficient as GSH is not orally bioavailable and is unstable in plasma due to the efficient catabolism by ?-glutamyl transpeptidase (GGT). To improve the utility of GSH supplementation for AD, we have developed a GSH analog (?-GSH) that is resistant to GGT. Our studies show that ?-GSH accumulates in the brain more efficiently than GSH and protects AD mouse model from onset of AD pathology. In the proposed studies, we will test the hypothesis that the GGT- resistant GSH-mimetic compounds will reduce oxidative stress and AGEs and slow/stop the progression of AD pathology in symptomatic stages of AD mouse models, including progressive neurodegeneration. Second, we aim to determine the role of Glo-1 enzyme system in AD pathogenesis and progression, and determine if Glo-1 enzyme is required for ?-GSH dependent neuroprotection. Finally, we propose to develop prodrugs of ?-GSH that will be more bioavailable than ?-GSH. The results of these studies will form a basis for rational design of druggable Glo-1 substrates and will provide strong justification for their continued development.